On June 22, 2017, the U.S. Food and Drug Administration granted regular approvals to dabrafenib and trametinib (TAFINLAR® and MEKINIST®, Novartis Pharmaceuticals Inc.) administered in combination for patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test.

These are the first FDA approvals specifically for treatment of patients with BRAF V600E mutation-positive metastatic NSCLC.

The FDA today also approved the Oncomine™ Dx Target Test (Thermo Fisher Scientific), a next generation sequencing (NGS) test to detect multiple gene mutations for lung cancer in a single test from a single tissue specimen. This test detects the presence of BRAF, ROS1, and EGFR gene mutations or alterations in tumor tissue of patients with NSCLC. This test can be used to select patients with NSCLC with the BRAF V600E mutation for treatment with the combination of dabrafenib and trametinib. This is the first NGS oncology panel test approved by the FDA for multiple companion diagnostic indications.

The approvals are based on Study BRF113928 (NCT01336634), an international, multicenter, three-cohort, non-randomized, non-comparative, open-label, trial in patients with locally confirmed BRAF V600E mutation-positive metastatic NSCLC. Ninety-three patients were treated with the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily). Of these 93 patients, 36 had received no prior systemic therapy for metastatic NSCLC and 57 received at least one platinum-based chemotherapy regimen with demonstrated disease progression. Seventy-eight patients with previously treated BRAF V600E mutation-positive NSCLC received single-agent dabrafenib.

In the previously treated group, the overall response rate (ORR) for the combination based on independent radiology review committee assessment per RECIST 1.1 was 63% (95% CI: 49%, 76%) with a median duration of response (DoR) of 12.6 months (95% CI: 5.8, not estimable [NE]). In the treatment-naive group, the ORR for the combination was 61% (95% CI: 44%, 77%) and median DoR was not estimable (95% CI: 6.9, NE); however, 59% of responders had response durations greater than six months. The ORR for patients who received single-agent dabrafenib was 27% (95% CI: 18%, 38%) and the median DoR was 9.9 months.

The incidence and severity of adverse reactions occurring in patients with NSCLC were generally similar to those reported in prior approvals for patients with melanoma. The most common adverse reactions (≥20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. The most common Grade 3-4 adverse reactions were pyrexia, fatigue, dyspnea, vomiting, rash, hemorrhage, and diarrhea. The majority of laboratory abnormalities were Grade 1-2. The most common (≥5%) Grade 3-4 laboratory abnormalities were hyponatremia, lymphopenia, anemia, hyperglycemia, neutropenia, leukopenia, hypophosphatemia, and increased alanine aminotransferase. Dabrafenib and trametinib were discontinued for adverse reactions in 18% and 19% of patients, respectively.

The recommended doses are dabrafenib 150 mg orally twice daily, approximately 12 hours apart, with trametinib 2 mg orally once daily. The presence of BRAF V600E mutation in tumor specimen should be confirmed by an FDA-approved test prior to initiation of therapy.

FDA granted Breakthrough Therapy Designation in 2015 for the combination of dabrafenib and trametinib for the treatment of patients with advanced and metastatic BRAF V600E mutation-positive NSCLC who received at least one prior line of platinum-containing therapy. Orphan Drug Designation was granted in 2014 to dabrafenib as a single agent for the treatment of patients with BRAF mutation positive NSLC and in 2015 combination with trametinib. A description of FDA expedited programs is available in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at MedWatch Online Voluntary Reporting Form, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).